Recurrent de novo BICD2 mutation associated with arthrogryposis multiplex congenita and bilateral perisylvian polymicrogyria

Gianina Ravenscroft, Nataliya Di Donato, Gabriele Hahn, Mark R. Davis, Paul D. Craven, Gemma Poke, Katherine R. Neas, Teresa M. Neuhann, William B. Dobyns, Nigel G. Laing

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


Autosomal dominantly inherited mutations of BICD2 are associated with congenital-onset spinal muscular atrophy characterised by lower limb predominance. A few cases have also showed upper motor neuron pathology, including presenting with features resembling hereditary spastic paraplegia. The age-of-onset for the published families is usually at birth but also included cases with childhood- and adult-onset disease. In this report we described two isolated probands that presented in utero with features associated with reduced fetal movements. Both cases were diagnosed at birth with arthrogryposis multiplex congenita (AMC) and hypotonia. Other variable features included congenital fractures, hip dislocation, micrognathia, respiratory insufficiency, microcephaly and bilateral perisylvian polymicrogyria. Patient 1 is 4 years of age and stable, but shows significant motor developmental delay and delayed speech. Patient 2 passed away at 7 weeks of age. Through next generation sequencing we identified the same missense substitution in BICD2 (p.Arg694Cys) in both probands. Sanger sequencing showed that in both cases the mutation arose de novo. The in utero onset in both cases suggests that the p.Arg694Cys substitution may have a more deleterious effect on BICD2 function than previously described mutations. Our results broaden the phenotypes associated with BICD2 mutations to include AMC and cortical malformations and therefore to a similar phenotypic spectrum to that associated with its binding partner DYNC1H1.

Original languageEnglish (US)
Pages (from-to)744-748
Number of pages5
JournalNeuromuscular Disorders
Issue number11
StatePublished - Nov 1 2016
Externally publishedYes

Bibliographical note

Funding Information:
The National Health and Medical Research Council of Australia (Early Career Researcher Fellowship APP1035955 to G.R. and Research Fellowship APP1002147 , EU Collaborative Grant APP1055295 and Project Grant APP1080587 to N.G.L.). This work was also supported by a grant from the Association Française contre les Myopathies ( 18724 ) and a FutureHealth WA Merit Award from the Department of Health .

Publisher Copyright:
© 2016


  • Arthrogryposis
  • BICD2
  • Fetal akinesia
  • Perisylvian polymicrogyria


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